The goal of this project is to develop an ultra sensitive liquid phase MS interface, based on the cylindrical capacitor ionization (CCI) technique which has recently been developed in the applicant's laboratory. The new CCI interface does not require an externally applied electric field around the spray tip, such as the metal needle and a counter electrode arrangement normally employed in electrospray ionization (ESI). The sample liquid is charged inside the capacitor instead of primarily at the spray tip. This charged liquid then can be sprayed into a space which may have a variety of pressure and electrical conditions present. The new design will limit corona discharge, and will allow one to put an ion focusing desolvation device near the spray tip, which can be below atmospheric pressure. This new design will have much better ion transmission efficiency relative to existing ESI sources. It will be less solvent dependent and more salt tolerant for most biological samples and will work equally well in positive and negative ion mode. Like electrospray, this new device will be applicable to many types of instruments, including quadrupole, quadrupole ion trap, Fourier transform, and time-of-flight MS. The signal/noise improvements observed for biomolecules are expected to be 10 to 500-fold. Preliminary data generated using a CCI front end, with an otherwise factory standard Finnigan heated capillary interface, indicated roughly a 500-fold improvement in concentration detection limits for the negative ion infusion analysis of diphosphorylated lipid A, at a flow rate of 50 nL/min. The greatest impact on biomedical research will be felt in the trace analysis of biomolecules that are difficult to spray, or that have relatively high detection limits, using existing electrospray technology. This would include many biological anions, or compounds that readily form anions in the gas phase, such as glycolipids, carbohydrates, nucleic acids, acidic proteins and acidic peptides. Improvements are also expected for the analysis of positive ions of biological origin.